TYROSINE KINASE AND MAPK INHIBITION OF TNF-ALPHA-STIMULATED AND EGF-STIMULATED IEC-6, CELL-GROWTH

The role of TNF-alpha in modulating intestinal crypt cell growth was e xamined, in comparison with EGF. Both significantly increased IEC-B ce ll proliferation. Neither EGF nor TNF-alpha overcame the inhibitory ef fect on growth exerted by the tyrosine kinase inhibitor genistein. Imm unoblots with phosphotyrosine antibodies showed increased tyrosine pho sphorylation of PEC-B cell proteins in response to EGF and TNF-alpha s timulation. TNF-alpha increased ERK1 and ERK2 MAPK phosphorylation. A MAPK assay confirmed the increased activity upon TNF-alpha stimulation . Selective inhibition of MAPK activation by PD98059 resulted in a dos e dependent inhibition of TNF-alpha or EGF-induced IEC-6 cell growth. These findings suggest a role for TNF-alpha in the regulation of intes tinal epithelial cell growth and that the mitogenic effect of TNF-alph a requires protein tyrosine phosphorylation and MAPK activation. (C) 1 998 Academic Press.